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PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

By Jie Li, Megan M. Kaneda, Jun Ma, Ming Li, Kunal Patel, Tomoyuki Koga, Aaron Sarver, Frank B. Furnari, Beibei Xu, Sanjay Dhawan, Jianfang Ning, Hua Zhu, Anhua Wu, Gan You, Tao Jiang, Andrew S. Venteicher, Jeremy N Rich, Christopher K Glass, Judith A Varner, Clark C Chen

Posted 16 May 2020
bioRxiv DOI: 10.1101/2020.05.14.097121

Precision medicine in oncology leverages clinical observations of exceptional response. Towards an understanding of the molecular features that define this response, we applied an integrated, multi-platform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted isoform of PI3K, PI3Kγ by pharmacologic inhibition or genetic inactivation, disrupted this signaling axis by suppressing microglia/macrophage accumulation and associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy. ### Competing Interest Statement The authors have declared no competing interest.

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